The present invention relates to a novel biodegradable polyphosphazene represented by Formula 1 that undergoes phase transition as the temperature changes and the preparation method thereof. More particularly, the present invention relates to a novel biodegradable polyphosphazene that undergoes a sol-gel or sol-solid phase transition as the temperature changes and the preparation method thereof. ##STR2##
(wherein X is O or NH, NHR is a depsipeptide selected from ethyl-2-(O-glycyl)glycolate (NHCH.sub.2 COOCH.sub.2 COOC.sub.2 H.sub.5) or ethyl-2-(O-glycyl)lactate (NHCH.sub.2 COOCH(CH.sub.3)COOC.sub.2 H.sub.5), NHR' is an amino acid ethyl ester selected from glutamic acid diethy ester (NHCH(CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5)COOC.sub.2 H.sub.5), phenylalanine ethyl ester (NHCH(C.sub.7 H.sub.7)COOC.sub.2 H.sub.5), valine ethyl ester (NHCH(CH(CH.sub.3).sub.2)COOC.sub.2 H.sub.5), or leucine ethyl ester (NHCH(CH.sub.2 CH(CH.sub.3).sub.2)COOC.sub.2 H.sub.5), NHR" is glycine ethyl ester (NHCH.sub.2 COOC.sub.2 H.sub.5) or alanine ethyl ester (NHCH(CH.sub.3)COOC.sub.2 H.sub.5) and a, b, c, d, e and f are mole fractions of each copolymer that have values between 0.about.1.0 with a relationship a+b+c+d+e+f=1.0. Also n is a degree of polymerization of polyphosphazene and is between 100.about.1000.)
A temperature-sensitive polymer refers to a polymer that undergoes a liquid to solid or liquid to gel phase transition, due to the large difference in solubility, as the temperature of the aqueous solution changes. The phase transition is reversible. At low temperatures, water molecules are bound to the hydrophilic moiety of the polymers by hydrogen bonding. As the temperature increases, the hydrogen bonding weakens resulting in a release of the water molecules, and the hydrophobic interaction becomes stronger during the process resulting in precipitation of the polymer. This type of phase transition temperature is called the lower critical solution temperature (LCST). Therefore, the phase transition temperature of the temperature-sensitive polymer increases as the content of the hydrophilic moiety in the polymer increases, and decreases as the content of the hydrophobic moiety increases. Studies for application using such thermosensitive polymers are actively underway in the fields of biomedical materials including drug delivery systems, environmental sciences, biological sciences, and cosmetics.
Thermosensitivity is reported for poly(N-isopropyl acrylamide) or polyethylene oxide copolymer, hydroxy group polymers and a number of polyphosphazenes (K. Park Eds, Controlled Drug Delivery, 485 (1997)). Most thermosensitive polymers, however are not degradable, and therefore are not suitable as a material for drug delivery (B. Jeong et. al., Nature, 388, 860 (1997)).
The present inventors have reported that poly(organophosphazenes), which can be obtained by substitution of polydichlorophosphazene with methoxy-poly(ethylene glycol) and amino acid ester, dissolve in water at low temperatures but precipitate out as a solid above the LCST and slowly hydrolyze in an aqueous environment (S. C. Song et. al., Macromolecules, 32, 2188 (1999)).
However, these synthetic polymers were found to be unsuitable as biomaterials since the LCST of most of these polymers are above the body temperature and their hydrolysis rate is too slow. Therefore, it was necessary to synthesize polymers having a desired hydrolysis rate and the LCST. Thus, the present inventors have found that polymers can be designed and synthesized to have the phase transition temperature and hydrolysis rate suitable as biomaterials by introducing a depsipeptide as a third side group and more hydrophobic amino acid ester in the polymer backbone. The LCST of thus synthesized polymers is in the vicinity of the body temperature, and the hydrolysis rate increases as the depsipeptide content increases.